Successfully delaying or preventing type 1 diabetes (T1D) will depend heavily on distinguishing those individuals that will progress to T1D among those individuals possessing high risk major histocompatibility complex alleles and/or titers for islet cell auto-antibodies (AA). Towards this goal, we have developed and applied a sensitive bioassay that measures the effect of serum or plasma on induced transcript levels in a well- controlled reporter peripheral blood mononuclear cell (PBMC) population. With this approach we have defined a recent onset (RO) T1D signature that includes genes regulated by interleukin-1, a cytokine that induces pancreatic -cell apoptosis in vitro and co-stimulates T-cells. This response is modulated by blocking IL-1 receptor in cultures and is distinct from that induced by samples of unrelated healthy controls, long- standing T1D patients, or patients possessing other diseases. So far, we have examined longitudinal samples of 9 progressors to T1D; in all cases the RO T1D signature was evident prior to onset. Importantly, this signature was detected in 3/3 cases where samples were available prior to AA development. Our data support the hypothesis that the dilute cytokine milieu associated with autoimmunity towards the pancreatic -cells is sufficient to induce a unique T1D-specific transcriptional profile; this signature reflects active autoimmunity, is disease specific, and may improve disease prediction beyond AA. In response to Program Announcement Response to PAR-11-350: Research Using Biosamples From Selected Type 1 Diabetes Clinical Studies (DP3) we propose this collaborative, multicenter study where the following aims will be perused to refine this mechanistically informative biomarker and define its predictive potential and utility: 1) Define the signature as a quantitative early biomarker for staging T1D progression. 2) Define disease-specificity of the T1D-signature.